Recently, immune suppressant agents have come into prominence because of their use during transplants of organs from one human to another, and in particular in connection with organ transplant operations such as heart and kidney transplants. It is part of the defense mechanism of humans to remove foreign antigens (in this case, produced by the transplanted organ) by the immune reaction. Thus, in all of the organ transplant operations, it has been necessary to give large doses of an immune suppressant prior to the operation and continuing thereafter in order to prevent the host from rejecting the donor organ.
The immune response is composed of a sequence of cellular transformations and biochemical events leading to a bimodal response to foreign substances (antigens). Cells which are to participate in the response evolve from stem cells which originate in the bone marrow and are seeded out to the peripheral lymphoid organs. From these latter sites, following antigenic stimulus, the body's response is mounted in the form of plasma cells (which produce antibody) and specific immune lymphocytes. Antibody is released into the circulatory system and thus may act at a distance from the producing cell (humoral immunity). Specific immune lymphocytes also enter the circulatory system and act at the site of injury (cellular immunity). The reaction of antibody with antigen triggers the release of histamine from basophilic leucocytes; histamine, in turn, alters the permeability of blood vessels, speeding the influx of both antibody and specific immune lymphocytes into the sites of injury. Thus, the immune response is composed of a series of biochemical events in a sequence of cells at various sites in the body. It can be altered -- suppressed, in the case of the compounds herein discussed -- at a number of biochemical or cellular developmental sites.
Antihistamines only affect a secondary reaction in the immune response, having no direct effect on antibody-producing cells or on specific immune lymphocytes. A number of agents, currently in use as immuno-suppressive drugs, act further back in the chain of events called herein the immune response. Certain anti-inflammatory steroids, e.g., cortisone, suppress production of antibody and specific immune lymphocytes, but also radically deplete normal lymphoid tissue and have other undesirable side effects. Certain antineoplastic drugs e.g., azathioprine, cyclophosphamide, and methotrexate, are employed as immunosuppressives, but they also deplete normal lymphoid tissue and radically depress other bone-marrow-derived cells. The general cytotoxicity of the latter drugs is to be expected in view of their having been selected on the basis of toxicity against a spectrum of cell types.
It is an object of this invention to provide novel compounds which alter the immune response in mammals by acting on cells functioning in the immune response, but which avoid certain side-effects and other undesirable attributes of compounds currently available as immune regulants.
Quinoxaline compounds are known in the art and can be prepared by the condensation of an aromatic o-diamine with a 1,2-diketone. The general preparation of quinoxalines is described in "The Chemistry of Heterocyclic Compounds," Vol. 5, Chapters 24-38 A. Weissberger, Ed., (Interscience Publishers, Inc. New York, 1953). When the diketones acenaphthalenequinone or phenanthrenequinone are condensed with o-phenylenediamines, the products are respectively acenaphtho[1,2-b]quinoxalines or dibenzo[a,c]phenazines. Acenaphtho[1,2-b]quinoxaline is described in Ber. 43, 441 (1910) and dibenzo[a,c]phenazine is described in Ann. 237, 341 (1887).
The acenaphtho[1,2-b]quinoxalines are named and numbered according to the Ring Index, The American Chemical Society, number 5998 and the dibenzo[a,c]phenazines are named and numbered according to the Ring Index, number 6221, as follows: ##STR1##